Utility of 99mTc-Sestamibi Single-Photon Emission Computed Tomography (SPECT)/CT Single Imaging Strategy in the Preoperative Localization of Parathyroid Adenoma

Background Primary hyperparathyroidism is an endocrinopathy associated with dysregulated calcium homeostasis. The most common etiology is a parathyroid adenoma most definitely managed via a parathyroidectomy. The two main surgical approaches include a minimally invasive parathyroidectomy (MIP) and open four-gland exploration (4-GE). MIP is the preferred operative strategy since it is associated with less postoperative complications. Accurate preoperative imaging is essential in informing the optimal approach to surgery. MIP is only considered if adenoma is able to be localized precisely. The most commonly used imaging modality includes ultrasound and sestamibi single-photon emission computed tomography (SPECT)/CT, either as a single or combination strategy. Other options include MRI, PET, and 4D CT. There is no universally accepted preoperative imaging strategy. The literature is discordant and recommendations proposed by existing guidelines are incongruous. Objectives This study aimed to evaluate currently utilized preoperative parathyroid imaging modalities at our institution and correlate them with surgical and histological findings to determine the most efficient imaging strategy to detect adenomas for our patient cohort. This will ultimately guide the best surgical approach for patients receiving parathyroidectomies. Methods This is a retrospective observational study of all patients undergoing first-time surgery for biochemically proven primary hyperparathyroidism at our institution over the past five years. Multiple data points were collected including modality of preoperative disease localization, operation type, final histopathology, biochemical investigations, and cure rate. Patients were categorized into one of three groups based on the method of disease localization. Results A total of 244 patients had parathyroidectomies performed at our institution in the past five years from January 2018 to December 2022. Ninety-six percent (n=235) of all patients received dual imaging preoperatively with SPECT/CT and ultrasound performed on the same day and therefore included in this study. A total of 64.3% (n=151) underwent MIP. Eighty percent (n=188) of all histopathology revealed adenomas and 26.8% (n=63) of patients had adenoma localized on SPECT/CT only (sensitivity: 58.1%, specificity: 71%, and positive predictive value {PPV}: 85.7%). A total of 9.8% (n=23) had adenoma localized on ultrasound only (sensitivity: 15.6%, specificity: 73.3%, and PPV: 65.2%). A total of 45.1% (n=106) were dual localized on both SPECT/CT and ultrasound (sensitivity: 75.6%, specificity: 46.6%, and PPV: 84.9%). The cure rate was 91.5% in the dual-localized group, 86% in the dual-unlocalized group, and 96.5% when localized with SPECT/CT alone. Conclusion A dual-imaging modality with SPECT/CT and ultrasound should remain the first-line imaging strategy. This approach has higher sensitivity rates and poses no inherent patient or surgical-related risks. Patients with disease unlocalized on SPECT/CT alone had a positive predictive value, specificity, and likelihood ratio for adenoma detection comparable to dual-localized patients. Therefore, SPECT/CT alone is sufficient for directing MIP in the presence of a negative ultrasound.


Introduction
Primary hyperparathyroidism (PHPT) is an endocrinopathy associated with the autonomous hyper-secretion 1 of parathyroid hormone (PTH) from one or more parathyroid glands, resulting in dysregulated calcium homeostasis [1].
It has an estimated incidence of 21 to 57 cases per 100,000 individuals per year and is most commonly diagnosed in adulthood.Globally, PHPT exhibits a prevalence of 0.84%, with a predisposition towards females and individuals of African-American descent.80% of affected individuals are asymptomatic while the remainder present with features of hypercalcemia [1].
PHPT is most commonly associated with PTH-producing adenomas (PTA).This can be sporadic or caused secondary to familial genetic pathologies like MEN1 syndrome [1].
Early diagnosis and appropriate management of PHPT is vital to prevent long-term consequences of hypercalcemia.The most definitive strategy for managing adenomas includes performing a parathyroidectomy.This can be performed minimally invasively (MIP) or via an open, four-gland exploratory approach (4-GE).
MIP offers several advantages, including reduced surgical duration, superior scar cosmesis, shorter postoperative hospitalisation, improved pain management, and diminished incidence of postoperative hypocalcemia.Consequently, MIP has emerged as the favoured surgical method amongst clinicians [2].
Accurate preoperative localisation of adenomatous glands is an indispensable prerequisite for justifying the adoption of a minimally invasive approach, as the initial operation plays a pivotal role in achieving a definitive cure and total treatment response.Gold standard treatment for adenoma driven PHPT includes accurate preoperative disease localisation and performance of a successful, totally curative MIP at first operation.Numerous imaging modalities are available for localising parathyroid pathology.Common options include ultrasound and Tc-99 sestamibi scintigraphy combined with various disease capture techniques such as computed tomography (CT), four-dimensional CT (4D CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and a variety of radiotracers.Of these, ultrasound and Tc-99 sestamibi SPECT/CT are the predominant preoperative parathyroid imaging modalities in clinical practice.
A comprehensive review of the existing literature on this subject matter reveals a notable discrepancy in the recommendations for optimal preoperative disease localization strategies.Divergent research findings have led to a lack of consensus.Presently, the primary guidelines governing preoperative imaging practices are those formulated by the National Institute for Health and Care Excellence (NICE) and the European Association of Nuclear Medicine (EANM) [4][5].
NICE guidelines advocate for ultrasound as the initial localization modality, with a subsequent sestamibi scan recommended if localisation fails.Conversely, EANM guidelines propose a combined approach involving single-isotope dual-phase Tc-99 sestamibi SPECT/CT and ultrasound.
Currently, at our institution, almost all patients receive dual imaging with both single-isotope dual-phase Tc-99 sestamibi SPECT/CT and ultrasound performed on the same day.The decision to proceed with MIP is contingent upon dual localisation on both imaging modalities.Modalities such as 4D CT are accessible but are not part of our routine preoperative imaging protocol.Unfortunately, our institution does not currently have access to MRI, PET, or other invasive diagnostic techniques for use in the preoperative localisation of parathyroid disease.
Ultimately, a universally accepted preoperative imaging strategy remains elusive, with practices varying from one institution to another.The existing literature is marked by discordant findings and recommendations from NICE and EANM exhibit incongruity.Consequently, the primary objective of this study is to assess the efficacy of the imaging modalities at our institution and correlate them with surgical and histological outcomes to discern the most efficacious imaging strategy for adenoma detection for our patient cohort.

Materials And Methods
A retrospective observational study was performed of all the parathyroidectomies performed at our institution over the past five years from January 2018 to December 2022.Local institutional ethical approval was not required as this is a retrospective observational study and a review of the current literature.All sensitive patient information was excluded and all data was anonymised as per institutional standards and protocols.
Our participant inclusion criteria included patients undergoing first-time surgery for biochemically proven PHPT who received both US and Tc-99 sestamibi SPECT/CT preoperatively as a mode of disease localization.Patients managed conservatively, those with a history of prior thyroid surgery, and those afflicted with secondary and/or tertiary hyperparathyroidism were excluded from the analysis.
An extensive parathyroidectomy database was constructed on Microsoft Excel 2016 which included a collection of multiple data points of all qualifying patients.This included demographic data like age, preoperative biochemical investigations like PTH, adjusted calcium, eGFR, vitamin D and urinary calcium.Modality of preoperative disease localisation was recorded as patients who had disease localised on US only, SPECT/CT only or on both ultrasound and SPECT/CT.The surgical approach of choice (MIP or 4-GE) and operation time of all patients was recorded.The histopathological findings following surgery were documented and categorised as parathyroid adenoma, hyperplasia, indeterminate, or normal.Postoperative PTH and adjusted calcium were also documented for each patient to establish treatment response and cure rate.
Following data collection, all patients were stratified into one of three distinct groups predicated on the modality of disease localisation.Patients localised on both SPECT/CT and ultrasound were put in the 'duallocalised cohort', whereas those localised using either SPECT/CT or ultrasound exclusively were allocated to the 'single-localised cohort.'Those with disease localised on neither SPECT/CT nor ultrasound were placed in the 'dual-unlocalised group' (see Figure 1).Comprehensive descriptive statistics, encompassing sensitivity, specificity, power calculations, predictive values, and likelihood ratios, were performed on Jamovi version 2.3.26.0.

Results
A total of 244 patients had parathyroidectomies performed at our institution in the past 5 years from January 2018 to December 2022.Among these patients, a noteworthy 96% received preoperative dual imaging with single-isotope dual-phase Tc-99 sestamibi SPECT/CT and US performed on the same day.The remaining 4% had data missing or received single modality imaging with SPECT/CT or US alone.Subsequently, 235 patients fulfilled the study inclusion criteria.The collective cohort exhibited an average reported age of 51 years, with the female gender constituting the majority at 71% (see Figure 2).64.3% (n=151) of patients received MIP while the remainder 35.7% (n=84) received 4-GE.Postoperative histopathological analysis revealed adenomas in 80% (n=188) of all parathyroidectomy cases, hyperplasia in 5.1% (n=12), normal findings in 9.8% (n=23), and indeterminate pathology in 5.1% (n=12) of cases.

FIGURE 2: Flowchart depicting adenoma incidence based on method of disease localisation
A subset analysis looking at sensitivity, specificity, predictive values and likelihood ratios for adenoma detection was performed relative to modality of disease localisation (see Table 1

Discussion
After processing all the data, a comparative analysis between all three patient cohorts was conducted.
When directly comparing detection rates between those with disease localised on SPECT/CT only relative to US, it was determined that localisation using SPECT/CT demonstrates a nearly fourfold increase in sensitivity compared to sole reliance on ultrasonography, while maintaining a commensurate level of specificity for adenoma detection (see Figure 3).Moreover, SPECT/CT exhibits a heightened positive predictive value in adenoma localisation relative to US (see Figure 4).It is noteworthy that the likelihood of identifying an adenoma in the presence of a positive SPECT/CT result is nearly four times more probable in comparison to US alone.Consequently, if a singular imaging strategy were to be employed, SPECT/CT is recommended as the preferred first-line imaging modality over US.This recommendation engenders considerable debate, as it contravenes the prevailing guidelines put forth by the National Institute for Health and Care Excellence, which advocates for US as the primary imaging modality of choice.
Furthermore, upon comparing patients whose disease was localised on both SPECT/CT and US with those solely on SPECT/CT, our analysis revealed that dual image localisation yielded 1.3 times higher sensitivity for adenoma detection compared to SPECT/CT alone (see Figure 5).In contrast, a converse observation was made regarding adenoma specificity between the two strategies, with a single-localising SPECT/CT exhibiting 1.5 times greater specificity relative to its dual-localising counterpart.Moreover, the PPV for adenoma detection was found to be comparable between single-imaging SPECT/CT and dual-imaging, standing at 85.7% and 84.9%, respectively (see Figure 6).

FIGURE 5: Sensitivity of adenoma localisation on single SPECT/CT versus dual imaging FIGURE 6: Positive predictive value of adenoma localisation on single SPECT/CT versus dual imaging
Our analysis revealed that the probability of identifying an adenoma in the presence of a positive SPECT/CT result alone, is nearly 1.5 times higher than disease localised on dual imaging.Furthermore, the postparathyroidectomy cure rate was observed to be 5% higher in the single SPECT/CT cohort compared to the dual localised group.
It can be devised from this descriptive analysis that SPECT/CT alone, despite offering similar sensitivity, exhibits superior specificity, positive predictive value, likelihood ratio, and cure rate when contrasted with patients with disease localised on both modalities.These findings lead to the conclusion that a single-localising SPECT/CT remains equally effective for adenoma localisation relative to a dual-imaging strategy.
Consequently, the consideration of MIP can be retained amongst patients with a positive SPECT/CT result in the presence of a negative US.This debates the recommendations outlined in the EANM guidelines, which advocate for second-line imaging strategies in the event of non-dual localisation prior to MIP, as well as NICE guidelines, which propose a 4-GE approach in cases of discordant results between both imaging.
In the subset of patients where the disease was localised using both SPECT/CT and US, a substantial 86.8% of individuals underwent MIP, while the remaining 13.2% received 4-GE.These 13.2% are presumed to represent a converted patient cohort, initially scheduled for MIP but subsequently shifted to 4-GE, either due to intra-operative failure of disease localisation or the emergence of other intra-operative complications necessitating an exploration.
For patients with disease localised exclusively via SPECT/CT, coupled with a negative result on US, a notable 76.2% received MIP.It is noteworthy that there was a 10% lower rate of MIP performed in this group relative to those who were dual-localised.Interestingly, this same group demonstrated a 10% higher incidence of 4-GE (see Figure 7).

FIGURE 7: Surgical approach based on modality of preoperative disease localisation
In light of our data, it is apparent that by converting a greater number of patients with single localising SPECT/CT to potential MIP candidates, we have the power to increase the rate of MIPs performed by an average of 10%.
It may be argued that if our data-driven analysis suggests that dual imaging yields only marginal additional benefits compared to a single localising SPECT/CT, then what justifies its retention as the primary imaging modality, instead of transitioning to a singular imaging approach with SPECT/CT alone?Some might consider performing an additional preoperative US without demonstrable added value as a misallocation of hospital resources and fiscal expenditure, introducing substantial inefficiency by impeding timely healthcare delivery.However, it is imperative to acknowledge that the dual imaging cohort displayed a 17% higher sensitivity rate for adenoma detection relative to SPECT/CT single localised patients.US results are subject to operator-dependent variability, with outcomes occasionally contingent on the proficiency and expertise of the sonographer which can be further improved.In addition, US is a noninvasive modality, and its integration as a standard in preoperative parathyroid imaging carries no inherent risk to the patient, ultimately justifying its continued use in clinical practice.
Among the cohort of 43 patients classified as dual-unlocalised, only two individuals were documented as having undergone supplementary second-line imaging, specifically 4D CT.These two patients subsequently underwent MIP and were histologically confirmed to have parathyroid adenomas.In contrast, the remaining 41 patients were presumed not to have received any second-line imaging modalities, as they exclusively underwent 4GE.Second line modalities like MRI and other specialised nuclear medicine modalities as preached in the literature like PET/CT with differing radiotracers are not available at our institution for use in parathyroid imaging.Regrettably, these techniques cannot be employed due to factors beyond the scope of this study.Our hospital has only one radiologist trained to interpret nuclear radiography, significantly limiting its utilisation and integration into our protocols.Although 4D CT is available, it is not employed as a routine imaging modality, and the precise reasons for this practice were not investigated.Invasive diagnostic techniques like FNAC and PVS are almost never performed due to risks associated with tumour seeding, infection, and scarring.

Limitations
The following study employs a retrospective observational design.This employs inherent biases and limitations associated with the analysis of historical data.Prospective studies with predefined protocols could offer more robust evidence.This could be a potential target for a future study.Moreover, all the study data was exclusively derived from a single institution which might not be representative of broader populations or practices.The findings of this study were not validated against external datasets which poses a selection bias that could restrict the generalizability of the findings and the applicability of the recommendations.Performing a multicenter study could help improve this limitation and eliminate bias.
As alluded to previously, the efficacy of US in adenoma localisation is intrinsically subjective and markedly contingent upon the skill and technique of the sonographer.This could have influenced the accuracy of disease localisation leading to higher or lower detection rates based on the performing sonographer.This is a bias that directly influences ultrasound's sensitivity and specificity rates.Repeating the study in a more standardized manner ensuring that all ultrasounds are performed by a single identified sonographer can help eliminate this bias.In addition, a meticulous and objective evaluation of the sonographer's proficiency and methodology can contribute substantially to resolving whether the limitations of US stem from operator skill or technical constraints.
Moreover, this study primarily focuses on preoperative imaging and immediate surgical outcomes.Longerterm follow-up data related to postoperative complications, recurrence rates, and patient quality of life would provide a more comprehensive assessment of the effectiveness of imaging strategies.

Conclusions
In conclusion, a universal and consistent algorithm for preoperative parathyroid imaging in the context of surgical planning for adenoma-related primary hyperparathyroidism remains elusive, as evidenced by the substantial disparities observed between the two primary guidelines.
Minimally invasive parathyroidectomy emerges as the preferred surgical approach in the majority of cases with localised disease.
Drawing from our institutional analysis, it is recommended that the dual-imaging strategy involving SPECT/CT and US be retained as the primary approach for adenoma localisation, provided there are no contraindications.This recommendation is underpinned by the strategy's superior sensitivity rates and its inherent absence of additional patient or surgical related risks.However, in circumstances necessitating the adoption of a single imaging modality, such as resource constraints or unavailability, SPECT/CT should assume precedence as the first-line imaging modality, with US as a secondary option.
PPV of adenoma detection in patients with disease localised on SPECT/CT and US is comparable to patients with disease localised on SPECT/CT only.Additionally, the SPECT/CT uni-localised group exhibits higher specificity rates, likelihood ratios for adenoma detection, and an overall cure rate when juxtaposed with the dual imaging cohort.Currently in our institution, the decision to proceed with MIP is contingent upon dual localisation on both imaging modalities.This analysis challenges the prevailing practice in our institution suggesting that SPECT/CT alone is sufficient for directing MIP in the presence of a negative ultrasound.